Inflammation and Treatment in Asthma and COPD

By James F. Donohue, MD, FCCP; and Jill A. Ohar, MD, FCCP

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Asthma

The Inflammatory Process in Asthma

Evidence that inflammation is a key component of asthma initially came from autopsy findings in patients with fatal asthma. Histologic examination revealed infiltration of the airways by neutrophils, eosinophils, and degranulated mast cells. Structural changes were visible as well; these included subbasement-membrane thickening, loss of epithelial cell integrity, and occlusion of the bronchial lumen by mucus. Hypertrophy and hyperplasia of airway smooth muscle and hyperplasia of goblet cells were also present. Additional information on the inflammatory component of asthma has been noted from endobronchial biopsies and BAL samples. These show an increase in the numbers of eosinophils, mast cells, and epithelial cells in asthmatics compared with both atopic and nonatopic persons without asthma. These inflammatory changes have been seen even in patients with mild disease.

The airway response to inhaled allergens forms the basis of much of our current understanding of the inflammatory process in asthma. After inhalation of an allergen by a patient with atopic asthma, bronchial obstruction can be seen in a matter of minutes. This early-phase response results primarily from the release of preformed proinflammatory mediators such as histamine and synthesis of leukotrienes C₄, D₄, and E₄ from bronchial mast cells. Mast cells arise in the bone marrow and travel to the mucosal and submucosal sites in the airways. The cross-linking of mast cell-bound IgE with allergen induces the activation of membrane and cytosolic pathways, leading to the release of mediators such as histamine and the synthesis of arachidonic acid metabolites. Mast cells respond to IgE-mediated and non-IgE-mediated (eg, osmotic) changes with the release of mediators. These include prostaglandins; leukotrienes; cytokines such as interleukin (IL) 1, IL-2, IL-4, IL-10, and IL-13; growth factors; and potent proteases such as trypsin.⁵ A recent study found that the infiltration of airway smooth muscle by mast cells is associated with disordered airway function in asthma, such as variable airflow obstruction and airway hyperresponsiveness.⁶ These mediators induce smooth muscle contraction, mucus secretion, and vasodilatation. Inflammatory mediators also induce microvascular leakage of plasma proteins, causing edematous swelling of the airway walls and a narrowing of the airway lumen. The early-phase allergic response usually resolves within 1 h, either spontaneously or with therapeutic intervention.

In many cases, a second phase of airflow obstruction, termed late-phase allergic response (LAR), occurs 6 to 10 h later. The LAR develops as a result of cytokines and chemokines generated by resident cells (mast cells, macrophages, and epithelial cells) and recruited inflammatory cells (T lymphocytes and eosinophils). The T lymphocytes involved in this process are Th₂, responsible for the immediate hypersensitivity reactions involved in allergic diseases, including asthma. The Th₂ subtype produces IL-4, IL-5, IL-6, IL-9, and IL-13; these cytokines have pronounced effects on inflammatory cells, particularly eosinophils. Eosinophils have an essential role in inflammation in asthma. IL-5 induces differentiation of immature eosinophils and stimulates their release from the bone marrow into the circulation and prolongs their survival. The eosinophil migrates from the circulation into the airway. On activation, the eosinophil releases inflammatory mediators such as leukotrienes and granule proteins such as major basic protein to injure airway tissues.

Features of the LAR include bronchospasm, further inflammation, and airway wall edema. Swelling of the airway wall also leads to a loss of elasticity, which further contributes to airflow limitation. An additional consequence of the LAR is an increase in airway hyperresponsiveness, which reinforces and perpetuates the asthmatic response.

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